PROJECT SUMMARY: Bipolar disorder (BD) can cause a great deal of suffering for individuals with the disorder and their families due to the acute mood episodes that also include a high risk of suicide, and the cognitive difficulties that can contribute to disability and impair prognosis. Unfortunately, the mechanisms underlying the acute mood episodes and the vulnerability to the switch between mood states, as well as cognitive dysfunction in the disorder, are not known, and current medications are often ineffective in treating mood episodes and cognitive difficulties. In order to provide more effective treatments for the mood episodes and cognitive difficulties in BD, and potentially prevent or reduce the onset or severity of acute episodes, it is necessary to elucidate the molecular mechanisms that underlie these features of the disorder. Preclinical and clinical evidence implicates the glutamatergic neurotransmitter system in BD, including data from magnetic resonance spectroscopy (MRS) studies showing altered levels of glutamate in depression or mania as compared to control group and positron emission tomography (PET) data from our group implicating the metabotropic glutamatergic receptors (mGluR5) in depressed and elevated mood states of BD. Unfortunately, most of the preclinical and clinical data come from studies of individuals with BD in the depressed mood state, and data during elevated mood state is sparse, limiting our understanding of the glutamatergic involvement in BD, and specifically its role in affective cycling. Thus, we propose an innovative study to examine glutamate neurotransmission (i.e., glutamate-glutamine cycling) in the prefrontal region of individuals with BD who are in depressed mood state or elevated mood state, and compare to healthy controls. State of the art isotopic 13C- MRS imaging with 13C-glucose methods will be used to measure glutamate neurotransmission in individuals with BD in depressed and elevated (manic/hypomanic) mood states and compare to those in healthy control individuals. The relationships between glutamate neurotransmission and glutamate levels will be correlated with measures of depressive and elevated mood symptoms, as well as with measures of PFC-related executive cognitive control of behavior. It is hypothesized that glutamate neurotransmission will be decreased in depression (and corresponding to higher glutamate levels during BD depression) but increased in elevated mood states (corresponding to lower glutamate levels during BD mania). We also hypothesize that the degree of abnormalities in the glutamate neurotransmission will be associated with the severity of mood symptoms and cognitive difficulties. These multidisciplinary results could lead to breakthrough in elucidating a process that may be important in the pathophysiology of BD, and one that can serve as a target for novel approaches for improved detection, treatment and prevention of BD.